TY - JOUR
T1 - Quantitative phosphoproteomic analysis of the molecular substrates of sleep need
AU - Wang, Zhiqiang
AU - Ma, Jing
AU - Miyoshi, Chika
AU - Li, Yuxin
AU - Sato, Makito
AU - Ogawa, Yukino
AU - Lou, Tingting
AU - Ma, Chengyuan
AU - Gao, Xue
AU - Lee, Chiyu
AU - Fujiyama, Tomoyuki
AU - Yang, Xiaojie
AU - Zhou, Shuang
AU - Hotta-Hirashima, Noriko
AU - Klewe-Nebenius, Daniela
AU - Ikkyu, Aya
AU - Kakizaki, Miyo
AU - Kanno, Satomi
AU - Cao, Liqin
AU - Takahashi, Satoru
AU - Peng, Junmin
AU - Yu, Yonghao
AU - Funato, Hiromasa
AU - Yanagisawa, Masashi
AU - Liu, Qinghua
N1 - Funding Information:
We are grateful to M. Dong, S. Chen and H. Mirzaei for mass spectrometry assistance; J. Cohen, R. Greene and F. Shao for comments on the manuscript. Q.L. is a W.A. 'Tex' Moncrief Jr. Scholar in Medical Research. Y.Y. is a Virginia Murchison Linthicum Scholar in Medical Research and a CPRIT scholar in Cancer Research. This work was supported by the Welch foundation (I-1608 to Q.L.; I-1800 to Y.Y.), the National Institute of Health (GM111367 to Q.L.; R01AG047928 to J.P.; GM114160 to Y.Y.), JSPS KAKENHI (16K16639 to Z.W.; 17K15592 to J.M.; 26220207, 17H06095 to M.Y., H.F., Q.L.; 17H04023, 16K15187, 15H05942 to H.F.), JST CREST (JPMJCR1655 to M.Y.), FIRST program from JSPS to M.Y., Uehara and Takeda Foundations to M.Y. and the WPI program from Japan's MEXT.
Funding Information:
Acknowledgements We are grateful to M. Dong, S. Chen and H. Mirzaei for mass spectrometry assistance; J. Cohen, R. Greene and F. Shao for comments on the manuscript. Q.L. is a W.A. ‘Tex’ Moncrief Jr. Scholar in Medical Research. Y.Y. is a Virginia Murchison Linthicum Scholar in Medical Research and a CPRIT scholar in Cancer Research. This work was supported by the Welch foundation (I-1608 to Q.L.; I-1800 to Y.Y.), the National Institute of Health (GM111367 to Q.L.; R01AG047928 to J.P.; GM114160 to Y.Y.), JSPS KAKENHI (16K16639 to Z.W.; 17K15592 to J.M.; 26220207, 17H06095 to M.Y., H.F., Q.L.; 17H04023, 16K15187, 15H05942 to H.F.), JST CREST (JPMJCR1655 to M.Y.), FIRST program from JSPS to M.Y., Uehara and Takeda Foundations to M.Y. and the WPI program from Japan’s MEXT.
Publisher Copyright:
© 2018 Macmillan Publishers Ltd., part of Springer Nature.
PY - 2018/6/21
Y1 - 2018/6/21
N2 - Sleep and wake have global effects on brain physiology, from molecular changes 1-4 and neuronal activities to synaptic plasticity 3-7. Sleep-wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep 8-11. Here we investigate the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and Sleepy mouse models of increased sleep need. Sleep deprivation induces cumulative phosphorylation of the brain proteome, which dissipates during sleep. Sleepy mice, owing to a gain-of-function mutation in the Sik3 gene 12, have a constitutively high sleep need despite increased sleep amount. The brain proteome of these mice exhibits hyperphosphorylation, similar to that seen in the brain of sleep-deprived mice. Comparison of the two models identifies 80 mostly synaptic sleep-need-index phosphoproteins (SNIPPs), in which phosphorylation states closely parallel changes of sleep need. SLEEPY, the mutant SIK3 protein, preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation of SNIPPs and slow wave activity during non-rapid-eye-movement sleep, the best known measurable index of sleep need, in both Sleepy mice and sleep-deprived wild-type mice. Our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and therefore SNIPP phosphorylation is a molecular signature of sleep need. Whereas waking encodes memories by potentiating synapses, sleep consolidates memories and restores synaptic homeostasis by globally downscaling excitatory synapses 4-6. Thus, the phosphorylation-dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep-wake homeostasis.
AB - Sleep and wake have global effects on brain physiology, from molecular changes 1-4 and neuronal activities to synaptic plasticity 3-7. Sleep-wake homeostasis is maintained by the generation of a sleep need that accumulates during waking and dissipates during sleep 8-11. Here we investigate the molecular basis of sleep need using quantitative phosphoproteomic analysis of the sleep-deprived and Sleepy mouse models of increased sleep need. Sleep deprivation induces cumulative phosphorylation of the brain proteome, which dissipates during sleep. Sleepy mice, owing to a gain-of-function mutation in the Sik3 gene 12, have a constitutively high sleep need despite increased sleep amount. The brain proteome of these mice exhibits hyperphosphorylation, similar to that seen in the brain of sleep-deprived mice. Comparison of the two models identifies 80 mostly synaptic sleep-need-index phosphoproteins (SNIPPs), in which phosphorylation states closely parallel changes of sleep need. SLEEPY, the mutant SIK3 protein, preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation of SNIPPs and slow wave activity during non-rapid-eye-movement sleep, the best known measurable index of sleep need, in both Sleepy mice and sleep-deprived wild-type mice. Our results suggest that phosphorylation of SNIPPs accumulates and dissipates in relation to sleep need, and therefore SNIPP phosphorylation is a molecular signature of sleep need. Whereas waking encodes memories by potentiating synapses, sleep consolidates memories and restores synaptic homeostasis by globally downscaling excitatory synapses 4-6. Thus, the phosphorylation-dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep-wake homeostasis.
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UR - http://www.scopus.com/inward/citedby.url?scp=85049049963&partnerID=8YFLogxK
U2 - 10.1038/s41586-018-0218-8
DO - 10.1038/s41586-018-0218-8
M3 - Article
C2 - 29899451
AN - SCOPUS:85049049963
SN - 0028-0836
VL - 558
SP - 435
EP - 439
JO - Nature
JF - Nature
IS - 7710
ER -